Tumor-targeted gene delivery of tumor necrosis factor-α induces tumor necrosis and tumor regression without systemic toxicity
Tumor-targeted gene delivery of tumor necrosis factor-α induces tumor necrosis and tumor regression without systemic toxicity
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DOI：
10.1038/sj.cgt.7700487
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发表时间：
2002-08-01
影响因子：
6.4
通讯作者：
Wagner, E
中科院分区：
文献类型：
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作者：
Kircheis, R;Ostermann, E;Wagner, E
我们最近开发了表面屏蔽的转铁蛋白-聚乙烯亚胺 (Tf-PEI)/DNA 递送系统，可在全身应用后将报告基因表达靶向远处的肿瘤。在本研究中，我们使用表面屏蔽的 Tf-PEI/DNA 复合物来传递高效细胞因子肿瘤坏死因子-α (TNFα) 的基因。 TNFα 以其诱导出血性肿瘤坏死和肿瘤消退的能力而闻名。然而，TNFα的治疗应用因其高全身毒性而受到阻碍，这决定了需要将TNFα活性靶向肿瘤。与非靶向复合物的应用相比，全身应用表面屏蔽的Tf-PEI与TNFα基因的复合物导致肿瘤中TNFα的优先表达，而没有可检测到的TNFα血清水平。在三种不同组织来源的小鼠肿瘤模型（Neuro2a 神经母细胞瘤、MethA 纤维肉瘤和 M-3 黑色素瘤）中，肿瘤靶向 TNFα 基因递送诱导明显的出血性肿瘤坏死并抑制肿瘤生长，并在 MethA 模型中观察到肿瘤完全消退。由于 TNFα 活性定位于肿瘤，因此未观察到全身性 TNF 相关毒性。靶向基因治疗可能是一种有吸引力的策略，适用于高活性但有毒的分子，例如 TNFα。
We have recently developed surface-shielded transferrin-polyethylenimine (Tf-PEI)/DNA delivery systems that target reporter gene expression to distant tumors after systemic application. In the present study, we used surface-shielded Tf-PEI/DNA complexes for delivering the gene for a highly potent cytokine, tumor necrosis factor-alpha (TNFalpha). TNFalpha is known for its ability to induce hemorrhagic tumor necrosis and tumor regression. However, the therapeutic application of TNFalpha is hampered by its high systemic toxicity dictating the need to target TNFalpha activity to the tumor. Systemic application of surface - shielded Tf-PEI complexes with the TNFalpha gene resulted in preferential expression of TNFalpha in the tumor without detectable TNFalpha serum levels, in contrast to the application of nontargeted complexes. Tumor-targeted TNFalpha gene delivery induced pronounced hemorrhagic tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origins, Neuro2a neuroblastoma, MethA fibrosarcoma, and M-3 melanoma, with complete tumor regressions observed in the MethA model. No systemic TNF-related toxicity was observed due to the localization of the TNFalpha activity to the tumor. Targeted gene therapy may be an attractive strategy applicable to highly active, yet toxic, molecules such as TNFalpha.